Gelatine is manufactured by the denaturation of collagen contained in materials such as pig skin, cattle skin or hide, and animal bones. Like its parent protein, collagen, gelatine is defined by a distinctive structure comprising a unique blend of amino acids. Native collagen is a scleroprotein based on a polypeptide chain comprising approximately 1050 amino acids. Three of these polypeptide chains come together to form a triple helix. Superimposition of several of these triple helices produces fibrils of collagen that are stabilized by cross-linking, hence forming a three-dimensional network structure. This particular structure renders collagen insoluble; it is then brought into soluble form by partial hydrolysis as gelatine or gelatine hydrolysate. The amino acid content of collagen and hence of gelatine, is about one third glycine and a further 22% proline and 4-hydroxyproline; the remaining 45% comprise 17 different amino acids. Gelatine has a particularly high content of acidic and basic amino acids. Of the acidic amino acids (glutamic acid and aspartic acid), variable amounts are present in the amido form as glutamine and asparagine depending on the processing conditions used in the gelatine manufacturing process. Cysteine is completely absent; of the sulphur-containing amino acids, methionine is the only one present.
The data for poultry and fish collagen are somewhat different, but the present invention is applicable likewise to gelatine and/or gelatine hydrolysate derived from poultry and fish collagen.
Gelatine can be utilized in a wide array of applications depending upon its starting material and method of manufacture. This is because the physical and chemical behavior of gelatine is determined on one hand by a combination of its amino acid content and the resulting spatial structure, and on another hand by a myriad of conditions such as pH, ionic strength and reactions with other molecules. For example, different kinds of gelatines are utilized in diverse applications such as food, photographic, cosmetic, and pharmaceutical.
In the pharmaceutical industry, gelatine is used inter alia in the manufacture of hard and soft capsules. Gelatine capsules provide a convenient and efficient method to orally administer a drug because the capsules disintegrate rapidly upon exposure to the acidic content of the stomach, thus releasing the drug into the body. While gelatine capsules provide a pharmaceutically elegant manner in which to administer a drug, there is, however, a risk that the gelatine capsule may suffer from retardation of disintegration and dissolution resulting from a process known as cross-linking. Cross-linking is believed to occur when carbonyl groups in gelatine, carbonyl-containing fill ingredients in capsules, or decomposition of fill ingredients into carbonyl groups, react with primary amines and other nitrogenous compounds present in gelatine to form cross-links.
Cross-linking, in particular, can have dire consequences on the performance of gelatine capsules upon extended storage and exposure to extremes of heat and humidity. Extensive gelatine cross-linking in capsule formulations may lead to the formation of a very thin, tough and water-insoluble film, usually referred to as a pellicle. The pellicle acts as a rubbery, water-insoluble layer that can restrict, or prevent release of the contents of the capsule.
One widely reported means to prevent cross-linking in gelatine capsules focuses on products that act as carbonyl scavengers, preventing the interaction of carbonyl groups, e.g., aldehyde groups, with the gelatine capsule shell, thus preventing gelatine cross-linking. These methods all generally suggest adding products to the pharmaceutical composition contained in the gelatine capsules. For example, it has been shown that adding the amino acid glycine and citric acid in combination to formulations encapsulated in gelatine hard capsules improved the dissolution profile of the hard capsules (3). Addition of the amino acid glycine alone was proven not to yield satisfactory results. But the addition of carbonyl scavengers such as glycine, and carboxylic acids such as citrate, in the amounts needed to reduce cross-linking in gelatine capsules is significantly cost prohibitive. As such, adding these products to gelatine is not a practical solution to reduce cross-linking in gelatine capsules.